POS0018 HUMAN MONOCLONAL ANTIBODIES DERIVED FROM GINGIVAL TISSUE B CELLS BIND MALONDIALDEHYDE (MDA)-MODIFIED SELF-PROTEINS AND EXACERBATES ARTHRITIS – A NOVEL AUTOIMMUNE LINK BETWEEN INFLAMED GUMS AND JOINTS
Authors: B. Raposo, C. De Vries, M. Gomes Afonso, P. Sahlström, L. Israelsson, R. Stålesen, L. Klareskog, V. Malmström, B. Réthi, C. Grönwall, K. Lundberg
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Based on an epidemiological association between periodontitis (PD) and rheumatoid (RA) arthritis<sup>[1]</sup>, with oral dysbiosis<sup>[2]</sup> and jawbone destruction<sup>[3]</sup> preceding the onset of RA, a causative link between periodontal infection and RA has been proposed. However, the mechanisms remain to be explained. Both gingival and synovial inflammation associate with malondialdehyde (MDA) protein modifications<sup>[4]</sup>, a posttranslational modification linked to oxidative stress. While MDA IgM are part of the natural antibody response, MDA IgG levels are elevated in RA and correlate with disease activity<sup>[5]</sup>. Moreover, RA joint B-cell derived MDA-reactive monoclonal antibodies (mAb) promote bone erosion and osteoclastogenesis<sup>[6]</sup>, suggesting pathogenic properties. Here we explore MDA-autoimmunity as an etiological link between inflamed gums and joints. <h3>Objectives</h3> To investigate if mAbs derived from gingival tissue (GT) B cells of PD patients bind MDA-modified self-proteins and whether they are pro-arthritogenic. <h3>Methods</h3> Recombinant mAbs (n=38) were generated as human IgG1 from single-cell sorted gingival tissue (GT) B cells of one PD patient with RA (PD/RA) and one PD patient without RA (PD only), and screened by ELISA for binding to MDA-modified and native albumin, fibrinogen and low-density lipoprotein. Three GT mAbs <i>versus</i> one isotype control mAb were assayed <i>in vitro</i> for TNF production by monocyte-derived macrophages stimulated by LPS (n=7 healthy donors), and two GT mAbs <i>versus</i> one isotype control mAb were examined <i>in vivo</i> in the collagen type II (CII) antibody-induced arthritis (CAIA) model (n=5 mice/group). Briefly, arthritis was induced in BALB/c mice by <i>i.v.</i> injection of 1.5mg anti-CII antibody cocktail together with 1mg GT or control mAb, followed by 25ug LPS on day 3. Arthritis scores and prevalence were recorded daily for two weeks; statistical analysis was performed using repetitive-measure one-way ANOVA with Geisser-Greenhouse correction and Holm-Šidák's multiple comparisons test. <h3>Results</h3> Three GT mAbs from the RA/PD patient and one from the PD-only patient bound MDA-modified self-proteins but not the native counterparts; all other GT mAbs were negative. The MDA-reactive GT B cell clones were class-switched (n=3 IgG+; n=1 IgA+) with 21-50 somatic hypermutations. The GT mAb with the strongest MDA-reactivity – derived from an IgA+ GT B cell isolated from the PD/RA patient – enhanced TNF production in LPS-stimulated macrophages, and exacerbated arthritis with prolonged arthritis, higher arthritis scores (p&lt;0.05) and higher disease prevalence (p&lt;0.001), see figure 1 below. <h3>Conclusion</h3> Here we show that MDA-autoreactive B cells with features of T-cell driven affinity maturation are present in the gum mucosa of PD patients with or without RA. Moreover, that antibodies from one such clone can exacerbate arthritis. Further studies are needed in order to elucidate the mechanisms involved, and to determine if possibly enhanced TNF production via antibody-mediated modulation of macrophage responses could play a role. Taken together, this pilot study supports further research into MDA-autoimmunity as an etiological link between periodontal infection and RA. <h3>References</h3> [1]Fuggle <i>et al</i>. <i>Front Immunol.</i> 2016, 2;7:80. [2]Cheng <i>et al. Ann Rheum Dis.</i> 2021, 80(2):162-168. [3]Kindstedt <i>et al. Arthritis Rheumatol.</i> 2018, 70(4):508-515. [4]Bright <i>et al. J Periodontal Res.</i> 2018, 53(1):139-143. [5]Grönwall <i>et al</i>. <i>Frontiers Immunol</i>. 2021, 12:627986. [6]Sakuraba <i>et al. J Autoimmun.</i> 2022, 133:102903. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.